RNA as a Therapeutic Target

The potential therapeutic value of targeting RNA is well recognized. But to date, intentionally targeting RNA has required oligonucleotide drugs, which have challenging pharmaceutical properties that have limited their utility for patients. Nevertheless, there are precedents for RNA-targeted small molecules (rSMs), including several approved drugs. In contrast to oligonucleotide drugs, these molecules were all discovered through serendipity; only after their discovery was it learned that they acted on RNA.

Emerging research has answered fundamental questions about the complex life of RNA and its suitability as a target for structure-based small molecule drug discovery. No longer an inconsequential intermediary between DNA and proteins, we now know that:

RNA folds into predictable and conserved secondary and tertiary structures that can be inferred from sequence.

The in vitro structure scan be demonstrated to match the structures within cells

RNA structures are diverse and dynamic but selectivity is achievable with small molecules

RNA structures are functionally significant, specifically influencing the translational efficiency of the RNA into protein

These properties of RNA allow us to deploy the principles of conventional structure-based drug design to rearchitect the drug discovery workflow for RNA to interrogate the transcriptome and to design rSMs to treat disease. We are screening thousands of RNA targets to deeply explore chemical and RNA structure space to build a unique understanding of the principles of RNA-small molecule interactions to select the most promising target/hit combinations to advance as therapeutic programs.

RNA pockets and dynamicsThe pockets and dynamics of RNA provide multiple opportunities to intervene in the life of an RNA to alter its function. RNA folds into complex three-dimensional pockets that are comparable to protein pockets and can be characterized computationally and experimentally. In addition, RNAs interconvert into multiple related conformations that can each be targeted by small molecules to differentially effect RNA function. Below shows the complex pockets and dynamics of AST-7.